Acrylic copolymer membranes for biosensors

ABSTRACT

Homogeneous membranes are disclosed which are composed of acrylic copolymers and are capable of absorbing 10% to 50% of their dry weight of water. The copolymers include a hydrophilic component which comprises acrylic esters having a poly(ethylene oxide) substituent as part of the alcohol moiety. The copolymers further comprise methacrylate and/or acrylate monomer units. The membranes are useful in the fabrication of biosensors, e.g., a glucose sensor, intended for in vivo use. Variations in the ratios of the monomeric components make possible the fabrication of membranes which have varying permeabilities.

This application is a division of U.S. patent application Ser. No.07/834,002, filed Feb. 11, 1992, now U.S. Pat. No. 5,284,140.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to homogeneous membranes composed of acryliccopolymers that are useful in the fabrication of biosensors intended forin vitro use, particularly glucose sensors.

2. Background of the Invention

Monitoring of many physiological parameters of medical significance isperformed in clinical chemistry laboratories which are remote from thepatient. Because of the time delay involved, the information obtained ishistorical and may not reflect the current state of the patient. As aconsequence, many researchers are attempting to develop biosensors to beused in vivo which would provide real time data for a number of analytesof clinical importance. An excellent summary of current research in thisarea has been published by Collison and Meyerhoff (Analytical Chemistry,62, 425-437, 1990).

A primary requirement of such sensors is that they be compatible withthe body. At a minimum, the materials used to fabricate the sensor mustnot exert any toxic or allergic effects on the body. In addition,sensors intended to be used in contact with blood must not provoke athrombotic reaction. Few polymer materials can meet the stringentrequirements of medical applications. Vadgama (Sensors and Actuators B1,Nos. 1-6, 1-7, 1990) has summarized the problems involved withinterfacing a biosensor with the biological environment.

A second requirement for biosensors intended for in vivo use is that thesensing element must exist in a stable environment. If the environmentthat the sensing element is exposed to is constantly changing, thesensor will experience "drift", and the values returned by the sensorwill be in error. Thus, the sensing element must be "protected" in someway from the harsh biological environment. This is generallyaccomplished by interfacing a membrane between the sensing element andits environment. Such membranes must be biocompatible or the reaction ofthe body, e.g., thrombosis or an inflammatory reaction, will result in acontinuing perturbation of the environment to which the sensing elementis exposed. Thus, biocompatibility of membranes used in the fabricationof biosensors is necessary not only for reasons of safety, but also inorder for the sensor to function at all. Wilkins and Radford (Biosensors& Bioelectronics, 5, No. 3, 167-213, 1990) have examined these issuesfor several biomaterials.

A final requirement, obviously, is that the sensor must accuratelymeasure the analyte of interest. The sensing element is potentiallyexposed to body proteins, electrolytes, medication being administered tothe patient, etc., any or all of which may interfere with themeasurement. Membranes, then, must not only be biocompatible, but theymust allow for accurate detection of the analyte of interest in thepresence of a number of chemical entities. Thus, permeability propertiesmust be matched to the design of the sensor as well as the analyte beingmeasured.

Considerable research is currently being directed toward the developmentof an in vivo glucose sensor. Such a sensor would make it possible tocontinuously monitor a patient's blood glucose levels and allow thephysician to develop therapy tailored to the individual. Most researchin this area is devoted to the development of electroenzymatic sensors.Such sensors are simpler and less expensive to fabricate than opticalsensors. One problem that must be overcome with such sensors is therequirement that the sensing element have access to a sufficient supplyof oxygen. The operational principle of these sensors is based on areaction between glucose and oxygen. Since the concentration of glucosein the body is much greater than that of oxygen, the local supply ofoxygen can become depleted unless some provision is made to control thereaction. These issues have been reviewed by Turner and Pickup(Biosensors, 1, 85-115, 1985).

The most favored configuration to date for an electrochemical glucosesensor involves the use of one or two enzymes to catalyze the reactionbetween glucose and another molecule in order to generate an electricalsignal. Typically, glucose oxidase is used to catalyze the reactionbetween glucose and oxygen to yield gluconic acid and hydrogen peroxide,as follows: ##STR1## The hydrogen peroxide generated may be detecteddirectly or it may be decomposed by a second enzyme, catalase, in whichcase the sensor will measure oxygen consumption by the reactioninvolving glucose oxidase.

A desirable feature of a membrane that will be used for glucose sensorsis the ratio of oxygen to glucose diffusion constants. It is not enoughto have a membrane which has a high oxygen diffusion constant. Siliconehas the highest permeability to oxygen of any polymer, but it is uselessas a membrane for glucose sensors because it is completely impermeableto glucose. Other membranes might have good permeability to oxygen buttoo much permeability to glucose. Thus, an ideal polymer system to beused for fabrication of members for a glucose sensor should allow forthe preparation of membranes with varying ratios of the diffusionconstants so as to be able to match the properties of the membrane tothe particular requirements of the sensor.

There remains a need for polymers which can be fabricated into membraneswhich meet the above requirements and which can have varying diffusionratios so that the membrane can be tailored to the specific requirementsof the sensor.

SUMMARY OF THE INVENTION

The membranes of the present invention possess unique attributes thatsatisfy the above objectives. Their properties can be varied to tailortheir diffusion characteristics to match the requirements of aparticular configuration of a biosensor. The homogeneous membranes ofthe invention are prepared from biologically acceptable copolymers whosehydrophobic/hydrophilic balance can be varied over a wide range. Themembranes are particularly useful in the construction of electrochemicalglucose sensors intended for in vivo use.

The membranes of the invention are fabricated from an acrylic copolymercomposed of two or more acrylic esters, one of which contains apoly(ethylene oxide) substituent as part of the alcohol moiety. Thepreferred acrylic copolymers so produced have a water pickup of fromabout 10% to about 50% of their dry weight of water. By appropriateselection of the reaction components, membranes can be made from thesecopolymers that can be used to fabricate biosensors intended for in vivouse.

The permeability characteristics of these membranes can be varied over awide range, making possible their use with a variety of biosensors whichdepend on the ability of the sensing element to accurately detect aspecific analyte. For example, ratios of the diffusion coefficients ofoxygen to glucose of up to about 4000, particularly with ratios of about2500 to about 3500, are preferred for membranes used with an in vivoglucose sensor.

These copolymers are soluble in a variety of solvents and solventcombinations, and thus can be readily fabricated into membranes ofvarious shapes. The membranes of the invention show good adhesion tosubstrates in an aqueous environment and possess excellent wet-strength.A further advantage of the copolymers from which the membranes of theinvention are fabricated is that they exhibit reduced toxicity inbiological systems, a key requirement for an implantable sensor of anytype.

Further and related objects and advantages of the present invention willbe apparent from the following description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic view of a glucose sensor having sensor elementswith an acrylic copolymer membrane of the present invention securedthereover.

FIG. 2 shows in schematic form an implantable portion of a glucosesensor, with the sensing elements covered with an acrylic copolymermembrane of the present invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

For the purposes of promoting an understanding of the principles of theinvention, reference will now be made to the preferred embodiments andspecific language will be used to describe the same. It willnevertheless be understood that no limitation of the scope of theinvention is thereby intended, such alterations and furthermodifications in the preferred embodiments, and such furtherapplications of the principles of the invention as illustrated therebybeing contemplated as would normally occur to one skilled in the art towhich the invention relates.

The present invention provides acrylic copolymer membranes for use incovering or encapsulating a biosensor, e.g., a glucose sensor,particularly one intended for in vivo use. It has been discovered thatthe use of such membranes provides many advantages including control ofdiffusion of the analytes/reactants to the sensor elements to permitaccurate analysis, protection of the sensor from the hostile in vivoenvironment, and biocompatibility.

The membranes of the present invention are prepared by conventionalmethods by the copolymerization of two or more acrylic ester monomers.The copolymers are soluble in solvents such as acetone, and may beformed as a membrane from solution by dip, spray or spin coating.

One of the acrylic ester monomers of the copolymer contains apoly(ethylene oxide), having an average molecular weight of about 200 toabout 2000, as the alcohol component of the acrylic ester. This monomeris referred to as the hydrophilic component of the copolymer.Particularly preferred is a poly(ethylene oxide) having an averagemolecular weight of about 1000. Examples of such monomers are themethoxy poly(ethylene oxide) monomethacrylates.

The other component(s) of the copolymer may be any of a number ofacrylic or substituted acrylic esters, especially the methacrylates andacrylates. Particularly preferred are methyl methacrylate alone or incombination with ethyl acrylate. As will be appreciated by those skilledin the art, variations in the choice of such monomers will influence theproperties of the membrane, particularly with regard to hydrophilicityand permeability. Selection of the comonomer(s) used in the membranesmay be readily determined by those skilled in the art, without undueexperimentation, to achieve the desired physical characteristics of themembranes. All other things being equal, monomers may be chosen on thebasis of commercial availability, cost, and ease of purification.

EXAMPLE 1 General Polymerization Procedure

Methods for preparing the membranes of the present invention are knownin the art. The following procedure provides a typical methodology.

18.75 g of methyl methacrylate, 6.25 g of methoxy poly(ethylene oxide)monomethacrylate (also known as methoxy polyethylene glycolmethacrylate) (MW 1000), 50 mg of 2,2'-azobisisobutyronitrile, and 50 mlof ethoxy ethyl acetate were added to a 200 ml pressure bottlecontaining a magnetic stirring bar. Nitrogen was bubbled through thestirred solution for 15 minutes. The bottle was then sealed and placedin an oil bath maintained at 75° C. The solution viscosity increasedwith time so that, after three hours, magnetic stirring stopped. After24 hours, the bottle was removed from the oil bath and allowed to coolto room temperature. The viscous solution was diluted with 50 ml ofacetone. The polymer product was precipitated from 1500 ml of hexane,redissolved in 100 ml of acetone and again precipitated from 1500 ml ofhexane. The white lump of polymer was soaked for 16 hours in 500 ml ofhexane. Finally, the polymer was dried for 16 hours at 50° C. in avacuum oven to yield 23.8 g of an off-white, brittle, solid mass.Additional representative polymers prepared by the above procedure arelisted in Table 1.

                  TABLE 1                                                         ______________________________________                                                          Methoxy                                                         Methyl        Poly(ethylene oxide)                                                                         Ethyl                                        #   Methacrylate (g)                                                                            Monomethacrylate (g)                                                                         Acrylate (g)                                 ______________________________________                                         1  10.65         3.75           10.65                                         2  10.00         5.00           10.00                                         3  15.00         5.00           5.00                                          4  12.50         6.25           6.25                                          5  15.00         10.00                                                        6  20.00         5.00                                                         7  18.75         6.25                                                         8  17.50         7.50                                                         9  16.25         8.75                                                        10  12.50         10.00          2.50                                         11  13.75         8.75           2.50                                         12  15.00         7.50           2.50                                         13  16.25         6.25           2.50                                         14  17.50         5.00           2.50                                         15  12.50         7.50           5.00                                         16  13.75         6.25           5.00                                         17  15.00         5.00           5.00                                         18  16.25         3.75           5.00                                         19  13.75         3.75           7.50                                         20  12.50         5.00           7.50                                         ______________________________________                                    

EXAMPLE 2

Molecular weight and water pickup were evaluated for selected polymersprepared in Example 1. Water pickup was determined on films 4.5 cm indiameter dried at 50° C. in vacuo, weighed, immersed in deionized waterfor 24 hours, removed and blotted with filter paper, and weighed.Percent water pickup was determined from the formula:

    % Pickup=[(W.sub.w -W.sub.d)/W.sub.d ]×100

where W_(w) is the weight of the swollen film and W_(d) is the weight ofthe dry film. The results are set forth in Table 2.

Molecular weights were determined by Gel Permeation Chromatography usinga Waters GPC I liquid chromatograph equipped with two WatersUltrastyragel® Linear columns, Waters Model R401 differentialrefractometer detector, and Waters Model 730 Data Module. Determinationswere run at 25° C. in toluene. Sample size was 250 microliters at aconcentration of 0.25% (w/v). Molecular weights were determined bycomparing retention times to a standard plot constructed by running aseries of nine polystyrene standards under the same conditions. Thus,reported molecular weights, set forth in Table 2, are "peak" molecularweights.

                  TABLE 2                                                         ______________________________________                                        NUMBER   MOLECULAR WEIGHT % WATER PICKUP                                      ______________________________________                                         5       115,000          63.2                                                 6       105,000          7.1                                                  7       100,000          16.2                                                 8       105,000          27.2                                                 9       100,000          37.2                                                10       110,000          78.8                                                11       115,000          56.5                                                12       105,000          35.9                                                13        96,000          22.3                                                14       105,000          12.9                                                15       105,000          58.8                                                16       130,000          35.5                                                17       125,000          19.8                                                18       110,000          12.3                                                19       135,000          20.2                                                20       180,000          32.8                                                21       270,000          59.8                                                22       125,000          8.8                                                 23       140,000          110.4                                               24       170,000          15.5                                                25       235,000          31.3                                                26       125,000          59.2                                                ______________________________________                                    

EXAMPLE 3

Membranes were prepared by casting films from a suitable solvent ontoglass using a Gardner knife (Gardner Labs). The solvent chosen dependson the particular chemical structure of the polymer. Acetone has beenthe preferred solvent in work completed to date, since it is readilyvolatile. Other suitable solvents include chloroform, dichloromethaneand toluene. After removal of the solvent, the membranes were hydratedwith deionized water for 30-60 minutes. They were then removed andtransferred to a Mylar* support sheet. Wet film thicknesses weremeasured with a micrometer before removal from the support.

Diffusion constants were measured in a standard permeability cell (CrownGlass Co., Inc.) maintained at 37.0° C., plus or minus 0.1° C., usingFick's relationship:

    J=-D dC/dx

where J is total flux, D is the diffusion constant, and dC/dx is theconcentration gradient across the membrane.

Oxygen diffusion constants were determined by securing the membrane withtwo rubber gaskets between the two halves of a diffusion cell maintainedat 37.0° C., plus or minus 0.1° C., and clamping the two halvestogether. Each side of the cell was filled with phosphate bufferedsaline. One side was saturated with nitrogen while the other side wassaturated with air. A calibrated oxygen sensor (Microelectrodes, Inc.)was placed in the nitrogen side of the cell, and measurements were takenat 5 minute intervals until the system reached equilibrium. Glucosediffusion constants were determined as above, except that one half ofthe cell was filled with phosphate buffered saline containing 300 mg/dlof glucose. The concentration of glucose in each half of the cell wasmeasured at appropriate intervals using a Cooper Assist ClinicalAnalyzer. The diffusion constants and ratios for sample polymers ofExample 1 are set forth in Table 3.

                  TABLE 3                                                         ______________________________________                                               D(CM2/SEC) × 10.sup.-6                                                                  RATIO                                                  POLYMER  OXYGEN     GLUCOSE    Doxygen/Dglucose                               ______________________________________                                         2       4.09       1.19       3.44                                            3       5.10       0.04       121.14                                          6       7.06       0.63       11.15                                           7       3.55       0.01       3550                                            9       3.44       0.09       40.47                                          10       4.51       0.22       20.69                                          11       5.74       1.09       5.27                                           12       5.51       0.75       7.35                                           13       4.42       0.17       26.00                                          14       5.73       0.08       69.04                                          16       6.23       0.77       8.09                                           17       6.85       0.61       11.23                                          21       5.56       0.26       21.38                                          22       5.51       1.10       5.01                                           24       5.99       360        0.02                                           26       5.65       8.90       0.63                                           27       7.10       280        0.03                                           ______________________________________                                    

The acrylic copolymers are effective, for example, in controlling thediffusion of analytes/reactants to a covered biosensor. By way ofexample, the polymer #7 was coated as an outer membrane on anelectroenzymatic glucose sensor. The sensor responded linearly toglucose in the concentration range of 0 to 400 mg/dl. The sensor did notshow an oxygen effect even at oxygen levels as low as 2%. Similarresults are achieved with the other copolymers of Example 1, as setforth in Table 3.

As demonstrated in the foregoing, the acrylic copolymers and resultingmembranes may be readily prepared having a wide range of diffusionconstants and water pickup. These formulations demonstrate the abilityto vary these parameters over the desired ranges previously described.This control enables one in the art to tailor the membranes toparticular biosensors.

EXAMPLE 4

Cytotoxicity testing was carried out on the acrylic copolymers ofExample 1 as follows. The test article size used was 64.3 cm² (1.0grams). A monolayer of L-929 mouse fibroblast cells was grown toconfluency and exposed to an extract of the test article prepared byplacing the test article in 11 ml of Minimum Essential Medium (Eagle)and Bovine Serum (5%) and extracting at 37° C. for 24 hours. An MEMaliquot was used as a negative control. After exposure to the extractfor 72 hours, the cells were examined microscopically for cytotoxiceffect. Presence or absence of a confluent monolayer, intracellulargranulation, cellular swelling, and crenation and the percentage ofcellular lysis were recorded.

IM implantation testing was carried out as follows. The test articlesize used was 1 mm wide and 10 mm long. Two healthy, adult New ZealandWhite rabbits weighing not less than 2.5 kg were used as test animals.Four strips of test material were introduced into the rightparavertebral muscle of each rabbit. Two strips of negative controlplastic were implanted in the left paravertebral muscle of each rabbit.The animals were humanely killed 7 days after implantation and theentire paravertebral muscle on each side of the spinal cord removed.Cross sections of the muscles were made to locate the implants. Thetissue surrounding each implant was examined macroscopically.

Hemolysis testing was also carried out on the acrylic copolymers ofExample 1. The test article size used was 1.0 grams, cut into smallchips. The sample was placed into each of two extracting tubescontaining 10 ml of Sodium Chloride Injection. To each tube was added0.2 ml of human blood previously collected in a vacuum tube containingE.D.T.A. Tubes were inverted gently to mix the contents, then placed ina constant temperature bath at 37° C. for one hour. The blood-salinemixture was then centrifuged for 10 minutes at 2200 RPM. The absorbanceof each sample solution was determined spectrophotometrically at 545 nmand compared to that of a positive control (10 ml water and 0.2 mlblood) and a negative control (10 ml Sodium Chloride Injection and 0.2ml blood) in order to determine the amount of hemoglobin released fromruptured red blood cells.

Results of the foregoing tests are set forth in Table 4.

                  TABLE 4                                                         ______________________________________                                                 CYTO-     HEMO-                                                      POLYMER  TOXIC     LYTIC    IM IMPLANTATION                                   ______________________________________                                         1       NO                 NOT SIGNIFICANT                                    2       NO                                                                    3       NO                 NOT SIGNIFICANT                                    4       NO                                                                    5       NO        NO       NOT SIGNIFICANT                                    6                 NO       NOT SIGNIFICANT                                    7       NO                                                                   10       NO        NO                                                         16       NO                                                                   17       NO                                                                   18       NO                                                                   19       NO                                                                   20       NO                                                                   21       NO                                                                   24       NO                                                                   25       NO                                                                   26       NO                                                                   ______________________________________                                    

The copolymers listed in Table 1 encompass a range of monomercompositions of varying molecular weights and water pickups (Table 2),all of which show excellent biocompatibility. The polymers used tofabricate these membranes must not exhibit any toxic or other harmfuleffects when placed in the body. Table 4 lists the results of assays forcytotoxicity, hemolysis, and irritation due to IM implantation ofrepresentative copolymers of the invention. As can be seen from theseresults, the copolymers exhibit excellent biocompatibility. Thecapability to vary the composition of the copolymer to achieve certainspecific properties, while maintaining biocompatibility, is also a keyfeature of this invention.

Particularly useful is the capability to moderate the permeability ofthese membranes toward particular analytes/reactants, e.g., oxygen andglucose. As can be seen from Table 3, representative copolymers of thisinvention show widely varying ratios of the diffusion constants ofoxygen to glucose, depending upon the monomer composition and the waterpickup. A major impediment to the development of an in vivo glucosesensor is the "oxygen deficit" problem. This arises from the fact thatthe concentration of oxygen in the body is much less than that ofglucose. As a consequence, a glucose sensor which depends, directly orindirectly, on measuring the change in oxygen concentration as a measureof the glucose concentration can become an oxygen sensor if the localsupply of oxygen is depleted. Thus the sensing element must exist in anenvironment in which it operates as a true glucose sensor. The membranesof this invention can provide such an environment, since they can betailored to provide optimum permeabilities of glucose and oxygen.

Referring to the drawings, there is shown in schematic form a biosensor10 of typical construction covered or encapsulated with a membranefabricated in accordance with the present invention. The specificconstruction and operation of the sensor 10 do not form a part of thepresent invention. For purposes of example but not to be limiting, theinventive membranes are described as used with a glucose sensor. Glucosesensors which utilize glucose oxidase to effect a reaction of glucoseand oxygen are known in the art, and are within the skill in the art tofabricate. The present invention depends not on the configuration of thebiosensor, but rather on the use of the inventive membranes to cover orencapsulate the sensor elements. Therefore, only a brief description ofan exemplary sensor is given herein.

The acrylic copolymer membranes of the present invention are useful witha variety of biosensors for which it is advantageous to controldiffusion of the analytes/reactants to the sensing elements. Varioussuch biosensors are well known in the art. For example, other sensorsfor monitoring glucose concentration of diabetics are described inShichiri, M., Yamasaki, Y., Nao, K., Sekiya, M., Ueda, N.: "In VivoCharacteristics of Needle-Type Glucose Sensor--Measurements ofSubcutaneous Glucose Concentrations in Human Volunteers"--Horm. Metab.Res., Suppl. Ser. 20:17-20, 1988; Bruckel, J., Kerner, W., Zier, H.,Steinbach, G., Pfeiffer, E.: "In Vivo Measurement of SubcutaneousGlucose Concentrations with an Enzymatic Glucose Sensor and a WickMethod," Klin. Wochenschr. 67:491-495, 1989; and Pickup, J., Shaw, G.,Claremont, D.: "In Vivo Molecular Sensing in Diabetes Mellitus: AnImplantable Glucose Sensor with Direct Electron Transfer," Diabetologia.32:213-217, 1989.

Sensor 10 includes a distal portion 11 in which are located sensorelements 12-14 which are connected through leads 15 to contacts 16.Typical sensing elements would be a counter electrode 12, workingelectrode 13 and reference electrode 14. Contacts 16 are connected witha suitable monitoring device (not shown), which receives signals andtranslates this information into a determination of the glucose leveldetected.

In this type of sensor, glucose oxidase is also provided in the areaadjacent the sensor elements, and catalyzes the reaction of glucose andoxygen. This, or a subsequent reaction, is monitored by the sensingelements, and a determination of glucose present in the surroundingsubcutaneous tissue may thereby be obtained.

In one design, the sensor 10 includes a substrate material 17 comprisingan electrical insulator. This substrate is preferably flexible tofacilitate patient comfort. The counter, working and referenceelectrodes 12-14 are positioned on the substrate and isolated from oneanother by an insulation layer 18 patterned to selectively expose theactive regions of the three electrodes. Glucose oxidase 19 is depositedon the working electrode and all three sensor/electrodes are thencovered with a membrane 20 of the present invention.

The distal portion of the sensor is implanted subcutaneously into thebody, and the proximal portion including contacts 16 remains external ofthe body. In accordance with the present invention, the implanted sensorelements 12-14 are covered with a membrane 20 of the present invention,which for the case of a glucose sensor is used to control the rate ofdiffusion of glucose and oxygen from the surrounding body tissue to thearea of the sensor elements. Membrane 20 may fully encapsulate theentire distal portion of the sensor or may simply be layered over thesensor elements. The latter approach may be preferable from thestandpoint of ease of fabrication.

The membranes of the present invention are readily formulated tooptimize the diffusion and water pickup characteristics for use withvarious biosensors. By way of example, membranes of the presentinvention having water pickups of about 10%, 30% and 50% have beenevaluated for use with an in vivo glucose sensor. In addition, theinventive membranes having oxygen to glucose diffusion ratios of about1000, 2000 and 3000 perform acceptably in the foregoing circumstances.The foregoing test results demonstrate that the membranes of the presentinvention satisfy the requirements for use with a variety of biosensors,namely biocompatibility, providing protection for the sensor elementsfrom the biological environment, and being modifiable to providecharacteristics of water pickup and permeability for variousanalytes/reactants to match a given application.

While the invention has been described in the foregoing description, thesame is to be considered as illustrative and not restrictive incharacter, it being understood that only the preferred embodiments havebeen described and that all changes and modifications that come withinthe spirit of the invention are desired to be protected.

What is claimed is:
 1. A homogeneous membrane adapted for use on abiosensor having sensor elements for evaluating the presence of ananalyte, said membrane being for enclosing the sensor elements, saidmembrane comprising:an acrylic copolymer including first monomer unitsconsisting of an acrylic ester having a poly(ethylene oxide) substituentas part of the alcohol moiety, and second monomer units selected frommethacrylates, acrylates and combinations thereof, said membraneabsorbing about 10% to about 50% of its dry weight of water.
 2. Themembrane of claim 1 in which said second monomer units comprise methylmethacrylate.
 3. The membrane of claim 1 in which said second monomerunits comprise ethyl acrylate.
 4. The membrane of claim 3 in which saidsecond monomer units further comprise methyl methacrylate.
 5. Themembrane of claim 1 in which said membrane absorbs about 15% to about25% of its dry weight of water.
 6. The membrane of claim 1 in which thepoly(ethylene oxide) substituent has an average molecular weight of fromabout 200 to about
 2000. 7. The membrane of claim 6 in which saidmembrane absorbs about 15% to about 25% of its dry weight of water. 8.The membrane of claim 6 in which the poly(ethylene oxide) substituenthas an average molecular weight of about
 1000. 9. The membrane of claim8 in which said poly(ethylene oxide) substituent comprises methoxypoly(ethylene oxide) methacrylate.
 10. The membrane of claim 1 in whichsaid membrane is adapted for use on an electrochemical glucose sensor,and in which said membrane has a ratio of its diffusion coefficient foroxygen to its diffusion coefficient for glucose of up to about
 4000. 11.The membrane of claim 10 in which said composition absorbs about 15% toabout 25% of its dry weight of water.
 12. The membrane of claim 10 inwhich the poly(ethylene oxide) substituent has an average molecularweight of from about 200 to about
 2000. 13. The membrane of claim 10 inwhich the diffusion ratio for said composition is about 2500 to about3500.
 14. The membrane of claim 13 in which said membrane absorbs about15% to about 25% of its dry weight of water.
 15. The membrane of claim13 in which the poly(ethylene oxide) substituent has an averagemolecular weight of from about 200 to about
 2000. 16. The membrane ofclaim 15 in which said membrane absorbs about 15% to about 25% of itsdry weight of water.
 17. In an implantable device for determining thelevel of an analyte in a body, said device comprising a biosensor havingsensor elements for evaluating the presence of the analyte and includinga membrane enclosing the sensor elements, said membrane providingbiocompatibility, protection of the sensor elements from the surroundingbiological environment, and control of diffusion of materials to thesensor elements, the improvement comprising forming said membrane froman acrylic copolymer comprising first monomer units consisting of anacrylic ester having a poly(ethylene oxide) substituent as part of thealcohol moiety, and second monomer units selected from methacrylates,acrylates and combinations thereof, said membrane absorbing about 10% toabout 50% of its dry weight of water.
 18. The improvement of claim 17 inwhich said second monomer units comprise methyl methacrylate.
 19. Theimprovement of claim 17 in which said second monomer units compriseethyl acrylate.
 20. The improvement of claim 19 in which said secondmonomer units further comprise methyl methacrylate.
 21. The improvementof claim 17 in which said membrane absorbs about 15% to about 25% of itsdry weight of water.
 22. The improvement of claim 17 in which thepoly(ethylene oxide) substituent has an average molecular weight of fromabout 200 to about
 2000. 23. The improvement of claim 22 in which thepoly(ethylene oxide) substituent has an average molecular weight ofabout
 1000. 24. The improvement of claim 17 in which said biosensor isan electrochemical glucose sensor, said membrane controlling thediffusion of oxygen and glucose to the sensor elements, said membranehaving a ratio of its diffusion coefficient for oxygen to its diffusioncoefficient for glucose of up to about
 4000. 25. The membrane of claim24 in which the diffusion ratio for said composition is about 2500 toabout
 3500. 26. The membrane of claim 24 in which said compositionabsorbs about 15% to about 25% of its dry weight of water.
 27. Themembrane of claim 24 in which the poly(ethylene oxide) substituent hasan average molecular weight of from about 200 to about
 2000. 28. Themembrane of claim 27 in which the poly(ethylene oxide) substituent hasan average molecular weight of about
 1000. 29. The membrane of claim 24in which said second monomer units comprise methyl methacrylate.
 30. Themembrane of claim 24 in which said second monomer units comprise ethylacrylate.
 31. The membrane of claim 30 in which said second monomerunits comprise methyl methacrylate.